Anti-arrhythmic drugs

How arrhythmias arise

The normal rhythmicity and error-free operation of the heart might be
considered a small miracle, given the complexity of the system! Unfortunately
when things do go wrong, they frequently go seriously wrong - many of us
will die an arrhythmic death.
There are many different ways to classify heart rhythm disturbances.
In managing these arrhythmias, we believe that one should be practical, and ask the following questions:

Is the arrhythmia fast or slow?

Is the origin of the rhythm disturbance ventricular or
supraventricular?

Is the patient haemodynamically compromised?

Does the arrhythmia need management?

What is the underlying substrate that predisposed to the
arrhythmia?

What triggered the arrhythmia?

Will the arrhythmia recur?

It is clear from the above list that assessment of the patient is
vital to understanding the arrhythmia. Careful assessment of the patient will give us valuable information
about the genesis of the rhythm disturbance, it's cardiovascular impact,
and appropriate therapy (if needed).

'Blocks and bradys'

One manifestation of disease affecting the myocardium may be impairment
of automaticity or conduction. We are fortunate in that generally if
one pacemaker fails, another normally subsidiary pacemaker takes over,
usually at a lower rate. Many factors can impair pacemaker automaticity
or myocardial impulse conduction - drugs such as beta blockers or sodium
channel blockers, electrolyte and pH disturbances, myocardial ischaemia or
hypoxia. (One always remembers that under anaesthesia, the first ten causes
of bradycardia are all hypoxia!). Anything that enhances parasympathetic
tone will likewise inhibit the rate of impulse formation and conduction.
Unfortunately, it's the much more sexy tachyarrhythmias that have excited
most interest - but don't forget that hundreds of thousands of pacemakers
are inserted every year for bradyarrhythmias!

Tachyarrhythmias

Despite the bewildering variety of tachyarrhythmias, there are just three
basic mechanisms, and of these, one predominates. They are:

Reentrancy

Increased automaticity

Triggered activity

Of these, re-entrancy seems to be coming more and more to the fore!
The basic concept is simple - an advancing impulse reaches a point (let's
call it X) where the wavefront has the possibility of moving along two different
pathways - as if it had come to a fork in the road. Unfortunately,
the impulse is blocked as it moves down the one limb (A), and passes unhindered
down the other limb (B). The key point is that the two limbs then join up
again, and at this point the impulse moves retrogradely up limb A. When
the impulse reaches point X again,
limb B is again able to conduct the impulse downwards, and the cycle
repeats itself. It is peculiar that the mechanism for one of the commonest
tachyarrhythmias is in part related to a 'boring old' block!

Note (and this is vital) that the initial block of the impulse as
it tried to move down limb A might be related to say the local peculiarities
of the conducting tissue, but frequently this block is simply related to
timing - limb A is not quite ready to receive another impulse, thank you
very much!

Also note that the heart is a dynamic, changing tissue. Although there
is an inherent risk in this dynamism (something can go wrong) often the
variablity in the heart is also its salvation (something that is wrong
can also 'spontaneously' go right). As we will discover, doctors have
probably accidentally killed an awful lot of people in discovering this
simple principle! Two examples are perhaps in order - we know that
there is normally a small, chaotic variability in the heart rhythm,
and that just prior to developing an episode of life-threatening
ventricular tachycardia, the heart often loses this variability and starts
to beat with metronome-like regularity. Secondly, we know from the CAST
study that 'Class IC antiarrhythmics' such as encainide, flecainide
and propafenone, despite decreasing the frequency with which arrhythmias
occur, appear to 'lock' those that do occur into a life-threatening
perpetuation!

Also note that because blocks are often transient and dependent on timing,
they need not even occupy a fixed anatomical location. Such a state
appears to prevail in at least some types of atrial fibrillation, where
we have multiple 'wavelets' moving around, propagating themselves and
combining.

Increased automaticity is easily understood. We know that
certain normal cardiac tissues have an inbuilt tendency to spontaneously
depolarise - it doesn't take much imagination to realise that similar
mechanisms might occur in other normally subservient muscle, and result
in 'ectopic' activity. This might occur following a variety of insults
- local ischaemia, hypokalaemia, or drugs such as digoxin, or indeed
a combination of such factors.

Triggered activity is a bit more special. The key concept here
is the 'afterdepolarisation' - after a normal action potential, the
cellular transmembrane potential suddenly swings positive again, and
if the timing and magnitude of this upswing is sufficient, a full
depolarisation may occur again. And again. And again! There are
(at least) two different mechanisms of triggered activity and these
result in

Early afterdepolarisations (EADs); or

Delayed afterdepolarisations (DADs)

Early afterdepolarisations occur before repolarisation has finished -
there is a sudden upswing in the transmembrane potential, which usually
occurs in the context of a prolonged action potential - for example,
with partial blockade of I K , the inward rectifying current
that normally terminates the action potential. DADs are different, as here
the membrane potential has returned to baseline when the upswing occurs.
DADs are thought to occur in relation to raised intracellular calcium
levels.

There are no rules that forbid a combination of the above to occur.
For example, in bad old monomorphic ventricular tachycardia, the
substrate for a re-entrant pathway might be a small myocardial scar
(for example, following a previous myocardial infarction). An extrasystole
occurring due to one of the other mechanisms might encounter the tissue
surrounding this scar in just the right state of refractoriness to
kick off a re-entrant circuit, which may then be perpetuated.

Membrane ion channels and their control

Excitable tissue works because it contains voltage-gated ion channels .
We know that there is normally an electrical potential of about -70mV or more
across cell-membranes, related to the difference in ionic concentrations
across the membrane. If this voltage is made less negative, a point is
eventually reached where the ion channels snap open (i.e. they are 'voltage
gated'). This allows a massive influx of sodium or calcium ions, making
the transmembrane potential even more positive - a classic example of
positive feedback.

Fortunately, the same trigger that set off the opening of the channels
soon results in their closing, and activation of a host of other mechanisms that
finally restore the cell membrane to its pristine state. If we look at
things from an evolutionary perspective, it seems that the first voltage-gated
ion channel was a calcium channel, and that sodium channels (which are faster)
and potassium channels (which are very special) diverged subsequently.
This divergence is mirrored in the different expression of channels (as
evolution seldom throws things away) - fast conducting tissues such as
Purkinje fibres rely on sodium channels, while cells that need to conduct
slowly (such as AV nodal cells) use calcium channels.

Ion channels and membrane pumps

Inward currents

Current

Mechanism

I Na

An inward voltage-gated channel,
the main driver of rapid depolarisation, the current only
lasting about 1ms. (I Na-B may
play a role in background current within SA nodal cells ?)
A small sub-population of sodium channels continue to open
during the action plateau!

I Ca-L

The main cardiac calcium channel,
found in most heart cells, contributing to depolarisation of SA
and AV nodal cells, and to the plateau of atrial, His-Purkinje
and ventricular cells. Blocked by verapamil, diltiazem and
dihydropyridines

I Ca-T

Occurs in pacemaker tissues,
possibly aiding the later part of spontaneous depolarisation of
atrial pacemaker tissue

I NS

This nonselective cation transporter
is gated by the intracellular concentration of Ca ++

In the resting state this small
current is active, turning off during depolarisation and then
back on again during repolarisation. Absent from atrial pacemaker cells!

I Kr

The rapid component of the "delayed
rectifier" that causes repolarisation of the membrane. Inhibited
by drugs such as dofetilide and amiodarone. There is also an
I Kur ultrarapid component of I K .

I Ks

The slow component of I K
- inhibited by amiodarone and azimilide

I K(Ach)

A current activated following
muscarinic (M 2 ) receptor stimulation. Also activated by
adenosine.

I K(ATP)

Normally blocked by ATP, this
channel opens up during ischaemia!

I K(Ca)

(Of questionable significance)

I to

A transient current that turns on
after depolarisation, and then soon turns off again - may contribute
to repolarisation heterogeneity! There may be two components (I to1
and I to2 ).

I Cl

(A small repolarising current
that is enhanced by adrenergic stimulation)

Pumps

I Na-K pump

An electrogenic pump that
generates a constant, tiny outward current

I Na/Ca

The current generated by this
pump is variable, depending on relative concentrations of Na +
and Ca ++ inside and outside the cell.

In order to restore things to their original state after a membrane
depolarisation, the ions that moved across the membrane have to be moved
back. A variety of active (energy-requiring) pumps exist to do this work.

The control of channel opening, closing and conductance is clearly
vital, and intricate. Many drugs can be used to manipulate these channels
either directly or indirectly. And one of our main traditional ways of
looking at anti-arrhythmic drugs relies on the concept of blockade of
these channels.

The Vaughan-Williams Classification

The much-maligned Vaughan-Williams classification of anti-arrhythmic
drugs is still going strong. It has the virtue of simplicity:

The Vaughan-Williams classification
of anti-arrhythmic drugs

Class

Mechanism of action

I

Sodium channel blockade

II

Beta adrenergic blockade

III

Prolongation of repolarisation
('Membrane stabilisation', often mainly due to potassium channel
blockade)

IV

Calcium channel blockade

See how three of the mechanisms are directly related to interference
with ion channels. Not content with the above simplicity, the Class I
agents are subdivided into three (IA, IB and IC) depending on
the effect of the agents on their precise effects on depolarisation and
repolarisation - IA slow depolarisation and conduction, and prolong
repolarisation, IB have little effect on phase 0 in normal fibres and shorten repolarisation, and IC have little effect on repolarisation
but profoundly depress both phase 0 depolarisation and conduction.
This subclassification matters little, as they are all pretty nasty
drugs!

A lot of fuss has been made about "state-dependent block" of
ion channels by various drugs (especially sodium channel blockers) -
the example always quoted is of lignocaine (which has a far greater
affinity for activated sodium channels, and 'lets go' rapidly with
a recovery time constant of under 1s once the channel is inactivated), and flecainide
which blocks about the same number of channels in both systole and diastole
owing to its recovery time constant of over ten seconds. The clinical
relevance of all this palpitation is far from clear.

The Sicilian Gambit (declined)

In late 1990, the Task Force of the Working Group on Arrhythmias of
the European Society of Cardiology (whew) got together in Taormina
and decided to revolutionise arrhythmia assessment. They called this
the "Sicilian Gambit". It hasn't yet quite caught on. The participants'
cardiology abilities seem better than their chess knowledge (a 'gambit' in
chess is a pawn sacrifice, and it's not immediately clear which pawn
is being sacrificed - perhaps the patient - or what arrhythmia
classification has to do with the Sicilian opening - ah - Taormina
is in Sicily).

The paper describing the SG is however worth reading (Circulation 1991
October 84.4 1831-51). The authors
make a valid criticism of the Vaughan-Williams classification on
several grounds (It's a mix of different mechanisms, many drugs fall
into multiple classes for example amiodarone, effects of agents might
differ depending on the underlying disease process, and its incomplete -
leaving out cholinergic agonists, adenosine, digoxin, alpha blockers,
and so on). They propose a 'framework' incorporating knowledge
of action of the agents, mechanisms of arrhythmia, and the "vulnerable
parameter" (target) that we hope to modify using a drug.

They break the discussion into three - first considering the
molecular and cellular targets of drug action, then how drugs affect
the mechanisms of arrhythmias, and finally the clinical context of
such drug use:

Targets
The different cell membrane channels, pumps and receptors are well-
discussed (brilliantly, for 1990). They go into considerable detail
about the effects of

Mechanisms
The authors regard the 'vulnerable parameter' as that single alteration
in electrophysiology that will terminate the arrhythmia (or prevent
its initiation) with minimal adverse effect. For increased normal
automaticity the vulnerable parameter is phase 4 depolarisation, and I f
is important, although modulating this is complex. With abnormal automaticity
I f becomes less important - as the maximum negative diastolic
potential drops to under about 50 mV I Ca becomes predominant,
and the vulnerable parameter should be the reduced maximum diastolic
potential, perhaps correctable by increasing K + efflux or
Na/K pump stimulation, or by attacking phase 4 depolarisation. Triggered
activity is complex - EADs are related to prolonged action potentials,
rationally managed by shortening the action potential duration; DADs,
commonly found with intracellular calcium overload are logically treated
using calcium channel blockers, or perhaps by blocking I NS
or increasing potassium conductance. Reentry is commonly managed by
blocking conduction or increasing refractoriness.

Clinical use
The authors provide a complex
table documenting the arrhythmia, mechanism, vulnerable parameter and
representative drugs that might be used. This table illustrates one of
the main problems with the Sicilian gambit - to apply it we need to understand the
genesis of arrhythmias better than we currently do!

Individual agents

Because of the complex actions of the various agents, doctors who prescribe
them should have a detailed knowledge of each agent prescribed, and the
suitability of such agents for the various arrhythmias. Here we simply
mention a few trends. This discussion would be incomplete without
mention of the apparent vast benefit of an implantable
cardioverter-defibrillator over conventional drug therapy
(e.g. MADIT and AVID).

Adenosine has become extremely popular in the management of
re-entrant supraventricular tachyarrhythmias. It activates I K(Ach),
transiently (under 5s) increasing AV nodal refractoriness, and often
terminating AV nodal reentrant tachyarrhythmias, where it's the drug
of choice. Side effects are usually relatively minor (flushing, occasional
precipitation of atrial fibrillation - the latter being a potential
problem in the presence of a fast-conducting accessory pathway). The major
problem is that if the underlying substrate has not been addressed, the
arrhythmia often recurs.

Class I agents have generally fallen into disfavour, notably in
patients with underlying ischaemic heart disease, notably following the
CAST study where mortality increased by 6%. Encainide and Propafenone
are occasionally used for maintenance of sinus rhythm in patients with
supra-ventricular arrhythmias such as atrial fibrillation provided there
is no underlying structural heart disease. Similar, infrequently used
agents with Class I actions are mexiletine, tocainide (which also
causes bone marrow aplasia / lung fibrosis), and moricizine. Lignocaine
is still useful for some acute ventricular arrhythmias, but its routine
use in ischaemic heart disease must be strongly condemned.

Amiodarone is becoming more popular, for both acute and chronic
management of both ventricular and supra-ventricular arrhythmias. It
is discussed in detail
elsewhere. Disadvantages include cost (especially
of the intravenous form) and the plethora of serious side effects seen with
chronic use. Amiodarone has actions in all four Vaughan-Williams classes,
but its predominant effect is Class III, due to block of both I Kr and
I Ks . Despite the prolongation of action potential duration, torsades
is distinctly unusual with amiodarone therapy. In the CHF-STAT trial
there was no lowering of mortality with amiodarone, but in GESICA
with a smaller sample size a 30% decrease in mortality was noted.

A number of new class III agents have been approved or are in
the pipeline. These include dofetilide (which selectively blocks
I Kr , and has been used with about 30% success for conversion of
chronic atrial fibrillation, and sinus rhythm maintenace - see
the DIAMOND trial), and ibutilide (only available in an intravenous form,
used for conversion of atrial fibrillation). Ibutilide has effects on
both sodium channels and I Kr .
Most have the side effect
of promoting the serious arrhythmia torsade de pointes, just like
the other commonly used class III agent, sotalol. Sotalol is racemic,
and the membrane-stabilising effects are seen at higher doses than
the beta blockade. It's pretty safe with myocardial dysfunction, perhaps
related to increased intracellular calcium levels improving contractility
somewhat. The ESVEM study showed the superiority of sotalol over
six different Class I agents.
Unfortunately the enantiomer d-Sotalol has not lived up to
expectation (nor did the patients treated with it - put to the
SWORD, as it were)!

Digoxin (digitalis glycosides) has a long and chequered history,
but the great wheel has again swung against it.
A lot of the chronic effect of digoxin may be related to increased vagal tone!
Disadvantages however include
the low therapeutic index, high incidence of proarrhythmia, and the fact
that it maintains atrial fibrillation rather than converting it to sinus
rhythm (which is generally now considered far more desirable).
Even where digoxin is used for rate control in AF, the rate often goes
crazy once the person exercises!

Bretylium is an unusual drug with a variety of complex actions,
initially releasing noradrenaline and then apparently blocking potassium
channels. It has always seemed to be an attractive drug because it may
lower defibrillation threshold in the fibrillating heart, but its role is
far from clear - too often physicians seem to administer it as the 'last
rites'!

Other agents:

Calcium channel blockers have fallen into disfavour for management
of supraventricular arrhythmias due to their negative inotropic effects,
and the odd misguided doctor who kills patients with ventricular
tachycardia by administering verapamil. For SVT, try adenosine.

Quinidine has both Class I and potassium-channel blocking
effects, and is occasionally used for maintenance of sinus rhythm in
atrial flutter or fibrillation. It also causes alpha blockade and
vagolysis.

intravenous Magnesium is regarded by many as the drug of choice for
torsade de pointes.

Procainamide is similar to quinine (without the alpha blockade and
vagolysis), is rapidly eliminated (necessitating use of slow-release
formulations), and causes lupus syndrome in slow acetylators. Enough
said.

Disopyramide is like quinidine but is anticholinergic, aninotropic
and may precipitate torsade de pointes.

Molecular Genetics - the long QT syndrome

Of great interest is the recent delineation of at least four different
hereditary syndromes characterised by myocardial ion channel abnormalities.
Clinically these manifest as a prolonged QT interval on surface ECG,
associated with early sudden death in some affected individuals.
Identified gene abnormalities include: